PANDORA: A Fast, Anchor-Restrained Modelling Protocol for Peptide: MHC Complexes

Abstract

Deeper understanding of T-cell-mediated adaptive immune responses is important for the design of cancer immunotherapies and antiviral vaccines against pandemic outbreaks. T-cells are activated when they recognize foreign peptides that are presented on the cell surface by Major Histocompatibility Complexes (MHC), forming peptide:MHC (pMHC) complexes. 3D structures of pMHC complexes provide fundamental insight into T-cell recognition mechanism and aids immunotherapy design. High MHC and peptide diversities necessitate efficient computational modelling to enable whole proteome structural analysis. We developed PANDORA, a generic modelling pipeline for pMHC class I and II (pMHC-I and pMHC-II), and present its performance on pMHC-I here. Given a query, PANDORA searches for structural templates in its extensive database and then applies anchor restraints to the modelling process. This restrained energy minimization ensures one of the fastest pMHC modelling pipelines so far. On a set of 835 pMHC-I complexes over 78 MHC types, PANDORA generated models with a median RMSD of 0.70 Å and achieved a 93% success rate in top 10 models. PANDORA performs competitively with three pMHC-I modelling state-of-the-art approaches and outperforms AlphaFold2 in terms of accuracy while being superior to it in speed. PANDORA is a modularized and user-configurable python package with easy installation. We envision PANDORA to fuel deep learning algorithms with large-scale high-quality 3D models to tackle long-standing immunology challenges.